JP2007525503A5 - - Google Patents
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- JP2007525503A5 JP2007525503A5 JP2007500824A JP2007500824A JP2007525503A5 JP 2007525503 A5 JP2007525503 A5 JP 2007525503A5 JP 2007500824 A JP2007500824 A JP 2007500824A JP 2007500824 A JP2007500824 A JP 2007500824A JP 2007525503 A5 JP2007525503 A5 JP 2007525503A5
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- 150000001875 compounds Chemical class 0.000 claims 77
- 239000000203 mixture Substances 0.000 claims 14
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims 11
- 125000003118 aryl group Chemical group 0.000 claims 10
- 238000000034 method Methods 0.000 claims 10
- 201000010099 disease Diseases 0.000 claims 9
- 229920000728 polyester Polymers 0.000 claims 9
- 125000000217 alkyl group Chemical group 0.000 claims 8
- 150000001412 amines Chemical class 0.000 claims 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 8
- 229910052736 halogen Inorganic materials 0.000 claims 7
- 150000002367 halogens Chemical class 0.000 claims 7
- 238000004519 manufacturing process Methods 0.000 claims 7
- -1 1,2-methylenedioxy Chemical group 0.000 claims 6
- 125000001931 aliphatic group Chemical group 0.000 claims 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 6
- 125000000623 heterocyclic group Chemical group 0.000 claims 6
- 125000004429 atoms Chemical group 0.000 claims 5
- 229910052799 carbon Inorganic materials 0.000 claims 5
- 125000006244 carboxylic acid protecting group Chemical group 0.000 claims 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 5
- 239000002253 acid Substances 0.000 claims 4
- 229910052739 hydrogen Inorganic materials 0.000 claims 4
- 230000001404 mediated Effects 0.000 claims 4
- 239000008194 pharmaceutical composition Substances 0.000 claims 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 4
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 3
- 230000001684 chronic Effects 0.000 claims 3
- 230000001808 coupling Effects 0.000 claims 3
- 238000010168 coupling process Methods 0.000 claims 3
- 238000005859 coupling reaction Methods 0.000 claims 3
- 125000001072 heteroaryl group Chemical group 0.000 claims 3
- 210000000056 organs Anatomy 0.000 claims 3
- 125000006239 protecting group Chemical group 0.000 claims 3
- 201000010874 syndrome Diseases 0.000 claims 3
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims 2
- 206010059512 Apoptosis Diseases 0.000 claims 2
- 208000003432 Bone Disease Diseases 0.000 claims 2
- 208000006454 Hepatitis Diseases 0.000 claims 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 2
- 230000006907 apoptotic process Effects 0.000 claims 2
- 125000004432 carbon atoms Chemical group C* 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- 231100000283 hepatitis Toxicity 0.000 claims 2
- 238000009169 immunotherapy Methods 0.000 claims 2
- 200000000018 inflammatory disease Diseases 0.000 claims 2
- 201000009251 multiple myeloma Diseases 0.000 claims 2
- 201000002674 obstructive nephropathy Diseases 0.000 claims 2
- 125000001424 substituent group Chemical group 0.000 claims 2
- 238000002054 transplantation Methods 0.000 claims 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 1
- 102100007495 AR Human genes 0.000 claims 1
- 101700046185 AR Proteins 0.000 claims 1
- 206010000880 Acute myeloid leukaemia Diseases 0.000 claims 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims 1
- 206010001897 Alzheimer's disease Diseases 0.000 claims 1
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- 208000009094 Anemia, Hemolytic, Autoimmune Diseases 0.000 claims 1
- 206010003210 Arteriosclerosis Diseases 0.000 claims 1
- 208000006673 Asthma Diseases 0.000 claims 1
- 206010003816 Autoimmune disease Diseases 0.000 claims 1
- 206010055128 Autoimmune neutropenia Diseases 0.000 claims 1
- 206010073080 Autoinflammatory disease Diseases 0.000 claims 1
- 206010004161 Basedow's disease Diseases 0.000 claims 1
- 206010068597 Bulbospinal muscular atrophy congenital Diseases 0.000 claims 1
- 206010007559 Cardiac failure congestive Diseases 0.000 claims 1
- 206010008120 Cerebral ischaemia Diseases 0.000 claims 1
- 208000008684 Chronic Thyroiditis Diseases 0.000 claims 1
- 206010009900 Colitis ulcerative Diseases 0.000 claims 1
- 210000004351 Coronary Vessels Anatomy 0.000 claims 1
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- 206010011401 Crohn's disease Diseases 0.000 claims 1
- 208000001490 Dengue Diseases 0.000 claims 1
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- 206010012601 Diabetes mellitus Diseases 0.000 claims 1
- 241000790917 Dioxys <bee> Species 0.000 claims 1
- 101700057458 Drice Proteins 0.000 claims 1
- 208000000718 Duodenal Ulcer Diseases 0.000 claims 1
- 206010014599 Encephalitis Diseases 0.000 claims 1
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- 206010015037 Epilepsy Diseases 0.000 claims 1
- 206010064570 Familial cold autoinflammatory syndrome Diseases 0.000 claims 1
- 206010016207 Familial mediterranean fever Diseases 0.000 claims 1
- 229940004296 Formula 21 Drugs 0.000 claims 1
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- 206010018651 Graft versus host disease Diseases 0.000 claims 1
- 208000009329 Graft vs Host Disease Diseases 0.000 claims 1
- 208000003807 Graves Disease Diseases 0.000 claims 1
- 201000004779 Graves' disease Diseases 0.000 claims 1
- 208000005721 HIV Infections Diseases 0.000 claims 1
- 208000005176 Hepatitis C Diseases 0.000 claims 1
- 206010019773 Hepatitis G Diseases 0.000 claims 1
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- 101700086956 IFNG Proteins 0.000 claims 1
- 102100016020 IFNG Human genes 0.000 claims 1
- 101700077335 IL18 Proteins 0.000 claims 1
- 102100009001 IL18 Human genes 0.000 claims 1
- 206010021972 Inflammatory bowel disease Diseases 0.000 claims 1
- 102000000589 Interleukin-1 Human genes 0.000 claims 1
- 108010002352 Interleukin-1 Proteins 0.000 claims 1
- 201000005807 Japanese encephalitis Diseases 0.000 claims 1
- 241000710842 Japanese encephalitis virus Species 0.000 claims 1
- 208000007766 Kaposi Sarcoma Diseases 0.000 claims 1
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- 208000001083 Kidney Disease Diseases 0.000 claims 1
- 206010024324 Leukaemias Diseases 0.000 claims 1
- 208000008456 Leukemia, Myelogenous, Chronic, BCR-ABL Positive Diseases 0.000 claims 1
- 208000007046 Leukemia, Myeloid, Acute Diseases 0.000 claims 1
- 206010027480 Metastatic malignant melanoma Diseases 0.000 claims 1
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- 241000721454 Pemphigus Species 0.000 claims 1
- 206010034674 Peritonitis Diseases 0.000 claims 1
- 208000009901 Polycystic Kidney Disease Diseases 0.000 claims 1
- 208000003055 Prion Disease Diseases 0.000 claims 1
- 210000001187 Pylorus Anatomy 0.000 claims 1
- 206010037660 Pyrexia Diseases 0.000 claims 1
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- 206010040070 Septic shock Diseases 0.000 claims 1
- 241000607768 Shigella Species 0.000 claims 1
- 206010040550 Shigella infection Diseases 0.000 claims 1
- 206010049771 Shock haemorrhagic Diseases 0.000 claims 1
- 241000580858 Simian-Human immunodeficiency virus Species 0.000 claims 1
- 208000008513 Spinal Cord Injury Diseases 0.000 claims 1
- 208000002320 Spinal Muscular Atrophy Diseases 0.000 claims 1
- 208000007107 Stomach Ulcer Diseases 0.000 claims 1
- 208000006011 Stroke Diseases 0.000 claims 1
- 102100003095 TNFRSF1A Human genes 0.000 claims 1
- 101710038526 TNFRSF1A Proteins 0.000 claims 1
- 206010043554 Thrombocytopenia Diseases 0.000 claims 1
- 206010043781 Thyroiditis chronic Diseases 0.000 claims 1
- 206010052779 Transplant rejections Diseases 0.000 claims 1
- 208000005765 Traumatic Brain Injury Diseases 0.000 claims 1
- 206010046851 Uveitis Diseases 0.000 claims 1
- 241000700605 Viruses Species 0.000 claims 1
- 208000006269 X-Linked Bulbo-Spinal Atrophy Diseases 0.000 claims 1
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- 230000001154 acute Effects 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 230000000240 adjuvant Effects 0.000 claims 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims 1
- 230000032683 aging Effects 0.000 claims 1
- 231100000360 alopecia Toxicity 0.000 claims 1
- 201000004384 alopecia Diseases 0.000 claims 1
- 201000001320 atherosclerosis Diseases 0.000 claims 1
- 201000008937 atopic dermatitis Diseases 0.000 claims 1
- 201000005000 autoimmune gastritis Diseases 0.000 claims 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 claims 1
- 201000009596 autoimmune hypersensitivity disease Diseases 0.000 claims 1
- 239000010836 blood and blood product Substances 0.000 claims 1
- 201000006474 brain ischemia Diseases 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 230000030833 cell death Effects 0.000 claims 1
- 201000006934 chronic myeloid leukemia Diseases 0.000 claims 1
- 201000006233 congestive heart failure Diseases 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 201000002949 dengue disease Diseases 0.000 claims 1
- 230000001066 destructive Effects 0.000 claims 1
- 201000009910 diseases by infectious agent Diseases 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 201000005917 gastric ulcer Diseases 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 201000010238 heart disease Diseases 0.000 claims 1
- 125000005349 heteroarylcycloalkyl group Chemical group 0.000 claims 1
- 125000005842 heteroatoms Chemical group 0.000 claims 1
- 201000001820 human immunodeficiency virus infectious disease Diseases 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 230000002757 inflammatory Effects 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 201000009673 liver disease Diseases 0.000 claims 1
- 201000009906 meningitis Diseases 0.000 claims 1
- 201000006417 multiple sclerosis Diseases 0.000 claims 1
- 201000003793 myelodysplastic syndrome Diseases 0.000 claims 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 125000006574 non-aromatic ring group Chemical group 0.000 claims 1
- 201000008482 osteoarthritis Diseases 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 230000000737 periodic Effects 0.000 claims 1
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- 231100000241 scar Toxicity 0.000 claims 1
- 230000036303 septic shock Effects 0.000 claims 1
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- 231100000331 toxic Toxicity 0.000 claims 1
- 201000008827 tuberculosis Diseases 0.000 claims 1
- 201000006704 ulcerative colitis Diseases 0.000 claims 1
- 239000003981 vehicle Substances 0.000 claims 1
- 0 CC(C1)C(O*)OC1=O Chemical compound CC(C1)C(O*)OC1=O 0.000 description 3
- OMTPLIZMNOGTKO-UHFFFAOYSA-N CCC1N2C1(C)C1CCC2CC1 Chemical compound CCC1N2C1(C)C1CCC2CC1 OMTPLIZMNOGTKO-UHFFFAOYSA-N 0.000 description 1
Claims (52)
ここで:
Yは、
である;
R1は、H、C1〜12脂肪族、C3〜10環状脂肪族、C6〜10アリール、5員〜10員ヘテロシクリル、5員〜10員ヘテロアリール、(C3〜10シクロアルキル)−(C1〜12脂肪族)−、シクロアルケニル−(C1〜12脂肪族)−、(C6〜10アリール)−(C1〜12脂肪族)−、(5員〜10員ヘテロシクリル)−(C1〜12脂肪族)−、または(5員〜10員ヘテロアリール)−(C1〜12脂肪族)−であり、ここで、任意の水素原子は、必要に応じて、別個に、R8で置き換えられ、そして同じ水素原子に結合した2個の水素原子の任意のセットは、必要に応じて、別個に、カルボニルで置き換えられる;
環Aは、以下である:
ここで、各環において、任意の水素原子は、必要に応じて、別個に、R4で置き換えられ、そして同じ水素原子に結合した2個の水素原子の任意のセットは、必要に応じて、別個に、カルボニルで置き換えられる;
環Aが、
であるとき、
Rは、R3C(O)−、HC(O)、R3SO2−、R3OC(O)、(R3)2NC(O)、(R3)(H)NC(O)、R3C(O)C(O)−、R3−、(R3)2NC(O)C(O)、(R3)(H)NC(O)C(O)またはR3OC(O)C(O)−である;そして
R3は、C1〜12脂肪族、C3〜10環状脂肪族、C6〜10アリール、5員〜10員ヘテロシクリル、5員〜10員ヘテロアリール、(C3〜10環状脂肪族)−(C1〜12脂肪族)−、(C6〜10アリール)(C1〜12脂肪族)−、(5員〜10員ヘテロシクリル)−(C1〜12脂肪族)−、または(5員〜10員ヘテロアリール)−(C1〜12脂肪族)−である;または、同じ原子に結合した2個のR3基は、その原子と一緒になって、3員〜10員芳香環または非芳香環を形成する;ここで、任意の環は、必要に応じて、C6〜10アリール、5員〜10員ヘテロアリール、C3〜10シクロアルキル、または5員〜10員ヘテロシクリルに縮合される;ここで、3個までの脂肪族炭素原子は、O、N、NR9、S、SOおよびSO2から選択される基で置き換えられ得、ここで、R3は、R8’から別個に選択される6個までの置換基で置換されている;
環Aが、
であるとき、
Rは、式IIで示すように、R3C(O)−であり、
そしてR3は、フェニル、チオフェンまたはピリジンであり、ここで、各環は、必要に応じて、R8’から別個に選択される5個までの置換基で置換されており、ここで、結合xに隣接した該フェニル、チオフェンまたはピリジン上の少なくとも1つの位置は、R12で置換され、ここで、R12は、5個以下の直鎖原子を有する;
R4は、ハロゲン、−OR9、−NO2、−CN、−CF3、−OCF3、−R9、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R9)2、−SR9、−SOR9、−SO2R9、−SO2N(R9)2、−SO3R9、−C(O)R9、−C(O)C(O)R9、−C(O)C(O)OR9、−C(O)C(O)N(R9)2、−C(O)CH2C(O)R9、−C(S)R9、−C(S)OR9、−C(O)OR9、−OC(O)R9、−C(O)N(R9)2、−OC(O)N(R)2、−C(S)N(R9)2、−(CH2)0〜2NHC(O)R9、−N(R9)N(R9)COR9、−N(R9)N(R9)C(O)OR9、−N(R9)N(R9)CON(R9)2、−N(R9)SO2R9、−N(R9)SO2N(R9)2、−N(R9)C(O)OR9、−N(R9)C(O)R9、−N(R9)C(S)R9、−N(R9)C(O)N(R9)2、−N(R9)C(S)N(R9)2、−N(COR9)COR9、−N(OR9)R9、−C(=NH)N(R9)2、−C(O)N(OR9)R9、−C(=NOR9)R9、−OP(O)(OR9)2、−P(O)(R9)2、−P(O)(OR9)2または−P(O)(H)(OR9)である;
R2は、−C(R5)(R6)(R7)、C6〜10アリール、5員〜10員ヘテロアリール、またはC3〜7シクロアルキルである;
R5は、HまたはC1〜6直鎖または分枝アルキルである;
R6は、HまたはC1〜6直鎖または分枝アルキルである;
R7は、−CF3、−C3〜7シクロアルキル、C6〜10アリール、5員〜10員ヘテロアリール、複素環、またはC1〜6直鎖または分枝アルキルであり、ここで、該アルキルの各炭素原子は、必要に応じて、別個に、R10で置換されている;
またはR5およびR7は、それらが結合する炭素原子と一緒になって、3員〜10員環状脂肪族を形成する;
R8およびR8’は、それぞれ別個に、ハロゲン、−OR9、−NO2、−CN、−CF3、−OCF3、−R9、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R9)2、−SR9、−SOR9、−SO2R9、−SO2N(R9)2、−SO3R9、−C(O)R9、−C(O)C(O)R9、−C(O)C(O)OR9、−C(O)C(O)N(R9)2、−C(O)CH2C(O)R9、−C(S)R9、−C(S)OR9、−C(O)OR9、−OC(O)R9、−C(O)N(R9)2、−OC(O)N(R9)2、−C(S)N(R9)2、−(CH2)0〜2NHC(O)R9、−N(R9)N(R9)COR9、−N(R9)N(R9)C(O)OR9、−N(R9)N(R9)CON(R9)2、−N(R9)SO2R9、−N(R9)SO2N(R9)2、−N(R9)C(O)OR9、−N(R9)C(O)R9、−N(R9)C(S)R9、−N(R9)C(O)N(R9)2、−N(R9)C(S)N(R9)2、−N(COR9)COR9、−N(OR9)R9、−C(=NH)N(R9)2、−C(O)N(OR9)R9、−C(=NOR9)R9、−OP(O)(OR9)2、−P(O)(R9)2、−P(O)(OR9)2および−P(O)(H)(OR9)である;
R9は、水素、C1〜12脂肪族、C3〜10環状脂肪族、C6〜10アリール、5員〜10員ヘテロシクリル、5員〜10員ヘテロアリール、(C3〜10環状脂肪族)−(C1〜12脂肪族)−、(C6〜10アリール)−(C1〜12脂肪族)−、(5員〜10員ヘテロシクリル)−(C1〜12脂肪族)−、またはヘテロアリール−(C1〜12脂肪族)−である;ここで、任意の水素原子は、必要に応じて、別個に、R8で置き換えられ、そして同じ水素原子に結合した2個の水素原子の任意のセットは、必要に応じて、別個に、カルボニルで置き換えられる;
R10は、ハロゲン、−OR11、−NO2、−CN、−CF3、−OCF3、−R11または−SR11である;ここで、R11は、C1〜4−脂肪族−である;
R11は、C1〜4−脂肪族−である;そして
R12は、ハロゲン、−OR11、−NO2、−CN、−CF3、−OCF3、−R11、−SR9である、
化合物。 Compounds of formula I:
here:
Y is
Is
R 1 is H, C 1-12 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C 3-10 cycloalkyl) -( C1-12 aliphatic)-, cycloalkenyl- ( C1-12 aliphatic)-, ( C6-10 aryl)-( C1-12 aliphatic)-, (5-membered to 10-membered heterocyclyl). -(C 1-12 aliphatic)-, or (5- to 10-membered heteroaryl)-(C 1-12 aliphatic)-, wherein any hydrogen atom is optionally separated separately , R 8 , and any set of two hydrogen atoms bonded to the same hydrogen atom is optionally replaced separately with carbonyl;
Ring A is:
Here, in each ring, any hydrogen atom is optionally replaced separately with R 4 , and any set of two hydrogen atoms bonded to the same hydrogen atom is optionally Separately replaced by carbonyl;
Ring A is
When
R is R 3 C (O) —, HC (O), R 3 SO 2 —, R 3 OC (O), (R 3 ) 2 NC (O), (R 3 ) (H) NC (O) , R 3 C (O) C (O) —, R 3 —, (R 3 ) 2 NC (O) C (O), (R 3 ) (H) NC (O) C (O) or R 3 OC (O) C (O)-; and R 3 is C 1-12 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5 membered to 10 membered heterocyclyl, 5 membered to 10 membered hetero. Aryl, (C 3-10 cycloaliphatic)-(C 1-12 aliphatic)-, (C 6-10 aryl) (C 1-12 aliphatic)-, (5-10 membered heterocyclyl)-(C 1-12 aliphatic) -, or (5- to 10-membered heteroaryl) - (C 1-12 aliphatic) - is; or two R 3 groups bonded to the same atom, the Together with the child, to form a 3-membered to 10-membered aromatic or non-aromatic ring; wherein any ring is optionally, C 6 to 10 aryl, 5-membered to 10-membered heteroaryl, C Fused to 3 to 10 cycloalkyl, or 5 to 10 membered heterocyclyl; wherein up to 3 aliphatic carbon atoms are a group selected from O, N, NR 9 , S, SO and SO 2 Can be substituted, wherein R 3 is substituted with up to 6 substituents independently selected from R 8 ′ ;
Ring A is
When
R is R 3 C (O) —, as shown in Formula II,
And R 3 is phenyl, thiophene or pyridine, wherein each ring is optionally substituted with up to 5 substituents independently selected from R 8 ′, wherein at least one position on the phenyl, thiophene or pyridine adjacent to x is substituted with R 12 , wherein R 12 has 5 or fewer linear atoms;
R 4 is halogen, —OR 9 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 9 , 1,2-methylenedioxy, 1,2-ethylenedioxy, —N (R 9 ) 2 , -SR 9 , -SOR 9 , -SO 2 R 9 , -SO 2 N (R 9 ) 2 , -SO 3 R 9 , -C (O) R 9 , -C (O) C (O) R 9, -C (O) C (O) OR 9, -C (O) C (O) N (R 9) 2, -C (O) CH 2 C (O) R 9, -C (S) R 9, -C (S) OR 9, -C (O) OR 9, -OC (O) R 9, -C (O) N (R 9) 2, -OC (O) N (R) 2, -C (S) N (R 9 ) 2, - (CH 2) 0~2 NHC (O) R 9, -N (R 9) N (R 9) COR 9, -N (R 9) N (R 9) C (O) OR 9 , -N (R 9) N (R 9 ) CON (R 9 ) 2 , —N (R 9 ) SO 2 R 9 , —N (R 9 ) SO 2 N (R 9 ) 2 , —N (R 9 ) C (O) OR 9 , —N (R 9) C (O) R 9, -N (R 9) C (S) R 9, -N (R 9) C (O) N (R 9) 2, -N (R 9) C (S ) N (R 9 ) 2 , —N (COR 9 ) COR 9 , —N (OR 9 ) R 9 , —C (═NH) N (R 9 ) 2 , —C (O) N (OR 9 ) R 9, -C (= NOR 9) R 9, -OP (O) (oR 9) 2, -P (O) (R 9) 2, -P (O) (oR 9) 2 or -P (O) (H) (OR 9 );
R 2 is —C (R 5 ) (R 6 ) (R 7 ), C 6-10 aryl, 5 membered to 10 membered heteroaryl, or C 3-7 cycloalkyl;
R 5 is H or C 1-6 linear or branched alkyl;
R 6 is H or C 1-6 linear or branched alkyl;
R 7 is —CF 3 , —C 3-7 cycloalkyl, C 6-10 aryl, 5-membered to 10-membered heteroaryl, heterocyclic, or C 1-6 straight or branched alkyl, where Each carbon atom of the alkyl is optionally substituted separately with R 10 ;
Or R 5 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered cycloaliphatic;
R 8 and R 8 ′ are each independently halogen, —OR 9 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 9 , 1,2-methylenedioxy, 1,2-ethylene. Dioxy, -N (R 9 ) 2 , -SR 9 , -SOR 9 , -SO 2 R 9 , -SO 2 N (R 9 ) 2 , -SO 3 R 9 , -C (O) R 9 ,- C (O) C (O) R 9 , —C (O) C (O) OR 9 , —C (O) C (O) N (R 9 ) 2 , —C (O) CH 2 C (O) R 9, -C (S) R 9, -C (S) OR 9, -C (O) OR 9, -OC (O) R 9, -C (O) N (R 9) 2, -OC ( O) N (R 9) 2 , -C (S) N (R 9) 2, - (CH 2) 0~2 NHC (O) R 9, -N (R 9) N (R 9) COR 9, -N (R 9) N (R 9) C ( ) OR 9, -N (R 9 ) N (R 9) CON (R 9) 2, -N (R 9) SO 2 R 9, -N (R 9) SO 2 N (R 9) 2, -N (R 9 ) C (O) OR 9 , —N (R 9 ) C (O) R 9 , —N (R 9 ) C (S) R 9 , —N (R 9 ) C (O) N (R 9 ) 2 , —N (R 9 ) C (S) N (R 9 ) 2 , —N (COR 9 ) COR 9 , —N (OR 9 ) R 9 , —C (═NH) N (R 9 ) 2 , -C (O) N (OR 9 ) R 9 , -C (= NOR 9 ) R 9 , -OP (O) (OR 9 ) 2 , -P (O) (R 9 ) 2 , -P ( O) (OR 9 ) 2 and —P (O) (H) (OR 9 );
R 9 is hydrogen, C 1-12 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C 3-10 cycloaliphatic. )-(C 1-12 aliphatic)-, (C 6-10 aryl)-(C 1-12 aliphatic)-, (5-10 membered heterocyclyl)-(C 1-12 aliphatic)-, or Heteroaryl- (C 1-12 aliphatic)-, wherein any hydrogen atom is optionally replaced separately by R 8 and two hydrogen atoms bonded to the same hydrogen atom Any set of may be separately replaced with carbonyl, if desired;
R 10 is halogen, —OR 11 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 11 or —SR 11 ; wherein R 11 is C 1-4 -aliphatic— Is
R 11 is C 1-4 -aliphatic ; and R 12 is halogen, —OR 11 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 11 , —SR 9 . ,
Compound.
ここで、R3は、フェニル、チオフェンまたはピリジンであり、ここで、各環は、必要に応じて、R8’から別個に選択される5個までの基で置換され、ここで、結合xに隣接した該フェニル、チオフェンまたはピリジン上の少なくとも1つの位置は、R12で置換され、ここで、R12は、5個以下の直鎖原子を有する、
化合物。 Compound of formula II
Wherein R 3 is phenyl, thiophene or pyridine, wherein each ring is optionally substituted with up to 5 groups independently selected from R 8 ′, wherein the bond x At least one position on the phenyl, thiophene or pyridine adjacent to is substituted with R 12 , wherein R 12 has 5 or fewer linear atoms;
Compound.
である、請求項1〜3のいずれか1項に記載の化合物。 Y is
The compound according to any one of claims 1 to 3, wherein
である、請求項1〜3のいずれか1項に記載の化合物。 Y is
The compound according to any one of claims 1 to 3, wherein
である、請求項1〜12のいずれか1項に記載の化合物。 Ring A is
The compound according to any one of claims 1 to 12, which is
である、請求項13に記載の化合物。 Ring A was optionally substituted with R 4
14. The compound of claim 13, wherein
である、請求項1〜12のいずれか1項に記載の化合物。 Ring A was optionally substituted with R 4
The compound according to any one of claims 1 to 12, which is
である、請求項15に記載の化合物。 Ring A was optionally substituted with R 4
16. The compound of claim 15, wherein
から選択される、化合物。 Less than:
A compound selected from:
a)請求項1〜28のいずれか1項に記載の化合物;および
b)薬学的に受容可能なキャリア、アジュバントまたはビヒクル。 A pharmaceutical composition comprising:
A) a compound according to any one of claims 1 to 28; and b) a pharmaceutically acceptable carrier, adjuvant or vehicle.
該組成物は、請求項1〜28のいずれか1項に記載の化合物または請求項29に記載の薬学的組成物を含有する、
組成物。 A composition for treating a disease in a patient, wherein the disease is an IL-1 mediated disease, an apoptosis mediated disease, an inflammatory disease, an autoimmune disease, an autoinflammatory disease, a destructive bone disorder, a proliferative disorder, Infectious diseases, degenerative diseases, diseases related to cell death, excessive edible alcohol consumption diseases, virus-mediated diseases, retinal disorders, uveitis, inflammatory peritonitis, osteoarthritis, pancreatitis, asthma, adult respiratory distress syndrome, glomerulonephritis , Rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic activity Hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, scar, graft-versus-host disease, organ transplant rejection, post-burn organ apoptosis, osteoporosis, leukemia and Disorder, myelodysplastic syndrome, multiple myeloma-related bone disorder, acute myeloid leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, hemorrhagic shock, sepsis, septic shock, burn, Shiga Shigella, Alzheimer's disease, Parkinson's disease, Huntington's disease, Kennedy disease, prion disease, cerebral ischemia, epilepsy, myocardial ischemia, acute and chronic heart disease, myocardial infarction, congestive heart failure, atherosclerosis, coronary artery Bypass transplantation, spinal muscular atrophy, amyotrophic lateral sclerosis, multiple sclerosis, HIV-related encephalitis, aging, alopecia, nerve damage caused by stroke, ulcerative colitis, traumatic brain injury, spinal cord injury, type B Hepatitis, hepatitis C, hepatitis G, yellow fever, dengue fever, Japanese encephalitis, various forms of liver disease, kidney disease, polycystic kidney disease, H pylorus-related gastric and duodenal ulcer, HIV infection Tuberculosis, meningitis, toxic epidermal necrosis, pemphigus, Maccle-Wells syndrome, familial cold urticaria, familial Mediterranean fever, chronic infantile neurocutaneous and joint syndrome, neonatal multisystem inflammatory disease, TNFR1-related periodic syndrome Or Hyper-IgD periodic fever syndrome;
The composition contains a pharmaceutical composition according to a compound or claim 29 according to any one of 請 Motomeko 1-28,
Composition .
a)移植目的の臓器;または
b)血液産物。 34. The method of claim 33, wherein the cell is present in:
a) an organ intended for transplantation; or b) a blood product.
ここで、Yは、
であり、そして他の変数は、請求項2〜11または13〜27のいずれか1項で定義したとおりである;
該プロセスは、アミンと酸(XがOHのとき)または適当な酸誘導体(Xが適当な脱離基のとき)とをカップリングする条件下にて、式1の化合物と式RXの化合物とを反応させて、式Iの該化合物を提供する工程を包含する:
ここで、該変数は、請求項2〜11または13〜27のいずれか1項で定義したとおりである;ここで、Xは、OHまたは適当な誘導体または脱離基である、
プロセス。 Process for preparing compounds of formula I:
Where Y is
And other variables are as defined in any one of claims 2-11 or 13-27;
The process comprises a compound of formula 1 and a compound of formula RX under conditions that couple an amine and an acid (when X is OH) or a suitable acid derivative (when X is a suitable leaving group). Reacting to provide the compound of formula I:
Wherein the variables are as defined in any one of claims 2-11 or 13-27; wherein X is OH or a suitable derivative or leaving group,
process.
ここで、Yは、
であり、そして他の変数は、請求項1〜11または13〜27のいずれか1項で定義したとおりである;
該プロセスは、アミンと酸(XがOHのとき)または適当な酸誘導体(XがOHではないとき)とをカップリングする条件下にて、式7−Aの化合物と式RNHCH(R2)C(O)Xの化合物とを反応させて、式Iの該化合物を提供する工程を包含する:
ここで、該変数は、請求項1、5〜9のいずれか1項で定義したとおりである;ここで、Xは、OHまたは適当な誘導体または脱離基である、
プロセス。 Process for preparing compounds of formula I:
Where Y is
And the other variables are as defined in any one of claims 1-11 or 13-27;
The process comprises a compound of formula 7-A and a formula RNHCH (R 2 ) under conditions that couple an amine and an acid (when X is OH) or a suitable acid derivative (when X is not OH). Reacting a compound of C (O) X to provide the compound of formula I:
Wherein the variables are as defined in any one of claims 1, 5-9; wherein X is OH or a suitable derivative or leaving group,
process.
ここで、該変数は、請求項1〜3または12〜27のいずれか1項で定義したとおりであり、該プロセスは、加水分解条件下にて、式Iの化合物を反応させて、式IIの化合物を提供する工程を包含する:
ここで、Yは、以下である:
ここで、R1は、請求項1または5〜9のいずれか1項で定義したとおりである、
プロセス。 Process for preparing compounds of formula IV:
Wherein the variables are as defined in any one of claims 1-3 or 12-27, and the process comprises reacting a compound of formula I under hydrolysis conditions to produce a compound of formula II Providing a compound of:
Where Y is:
Wherein R 1 is as defined in any one of claims 1 or 5-9.
process.
ここで、PG1は、適当なカルボン酸保護基である;PG2は、適当な窒素保護基である;そして環Aは、請求項1で定義したとおりである;該プロセスは、以下の工程を包含する:
アミンとカルボン酸(XがOHであるとき)またはアミンと適当なカルボン酸(Xが適当な脱離基であるとき)とをカップリングする条件下にて、式2−Aの化合物と:
式20−Aの化合物とを反応させて、式3−Aの化合物を提供する工程:
ここで、Xは、OHまたは適当な脱離基である、
プロセス。 Process for preparing compounds of formula 3-A:
Where PG 1 is a suitable carboxylic acid protecting group; PG 2 is a suitable nitrogen protecting group; and ring A is as defined in claim 1; the process comprises the following steps: Includes:
Under conditions for coupling an amine and a carboxylic acid (when X is OH) or an amine and a suitable carboxylic acid (when X is a suitable leaving group) with a compound of formula 2-A:
Reacting a compound of formula 20-A to provide a compound of formula 3-A:
Where X is OH or a suitable leaving group,
process.
ここで、PG1は、適当なカルボン酸保護基であり、そしてPG2は、適当な窒素保護基である;該プロセスは、以下の工程を包含する:
アミンとカルボン酸(XがOHであるとき)またはアミンと適当なカルボン酸(Xが適当な脱離基であるとき)とをカップリングする条件下にて、式2−Aの化合物と:
式20の化合物:
とを反応させて、式3の化合物を提供する工程。 Process for preparing the compound of formula 3:
Where PG 1 is a suitable carboxylic acid protecting group and PG 2 is a suitable nitrogen protecting group; the process includes the following steps:
Under conditions for coupling an amine and a carboxylic acid (when X is OH) or an amine and a suitable carboxylic acid (when X is a suitable leaving group) with a compound of formula 2-A:
Compound of formula 20:
To provide a compound of formula 3.
ここで、PG1は、適当なカルボン酸保護基であり、そしてPG2は、適当な窒素保護基である;
該プロセスは、以下の工程を包含する:
アミンとカルボン酸(XがOHであるとき)またはアミンと適当なカルボン酸(Xが適当な脱離基であるとき)とをカップリングする条件下にて、式2の化合物と:
式21の化合物:
とを反応させて、式13の化合物を提供する工程。 Process for preparing compounds of formula 13:
Where PG 1 is a suitable carboxylic acid protecting group and PG 2 is a suitable nitrogen protecting group;
The process includes the following steps:
Under conditions for coupling an amine and a carboxylic acid (when X is OH) or an amine and a suitable carboxylic acid (when X is a suitable leaving group) with a compound of formula 2:
Compound of formula 21:
To provide a compound of formula 13.
ここで、PG1は、適当なカルボン酸保護基である;PG2は、適当な窒素保護基である;そしてR1は、請求項1または5〜9のいずれか1項で定義したとおりである、
化合物。 Compound of formula 5-A:
Wherein PG 1 is a suitable carboxylic acid protecting group; PG 2 is a suitable nitrogen protecting group; and R 1 is as defined in any one of claims 1 or 5-9. is there,
Compound.
ここで、Zは、Z−型保護基であり、そしてPG1およびR1は、請求項40で定義したとおりである、
化合物。 Compound of formula 5:
Wherein Z is a Z-type protecting group and PG 1 and R 1 are as defined in claim 40,
Compound.
ここで、PG1は、適当なカルボン酸保護基であり、そしてPG2は、適当な窒素保護基である、
化合物。 Compound of formula 15:
Where PG 1 is a suitable carboxylic acid protecting group and PG 2 is a suitable nitrogen protecting group,
Compound.
ここで、PG1、PG2およびR1は、請求項43で定義したとおりである、
化合物。 Compound of formula 3-A:
Where PG 1 , PG 2 and R 1 are as defined in claim 43,
Compound.
ここで、Zは、Z−型保護基であり、そしてPG1は、請求項43で定義したとおりである、
化合物。 Compound of formula 3:
Wherein Z is a Z-type protecting group and PG 1 is as defined in claim 43,
Compound.
ここで、PG1およびPG2は、請求項43で定義したとおりである、
化合物。 Compound of formula 13:
Where PG 1 and PG 2 are as defined in claim 43,
Compound.
ここで、PG1およびPG2は、請求項43で定義したとおりである、
化合物。 Compound of Formula 4A:
Where PG 1 and PG 2 are as defined in claim 43,
Compound.
ここで、Zは、Z−型保護基であり、そしてPG1、は、請求項43で定義したとおりである、
化合物。 Compound of formula 4:
Wherein Z is a Z-type protecting group and PG 1 is as defined in claim 43,
Compound.
ここで、PG1およびPG2は、請求項43で定義したとおりである、
化合物。 Compound of formula 14:
Where PG 1 and PG 2 are as defined in claim 43,
Compound.
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KR101135765B1 (en) * | 2004-03-12 | 2012-04-23 | 버텍스 파마슈티칼스 인코포레이티드 | Processes and intermediates for the preparation of aspartic acetal caspase inhibitors |
ZA200610133B (en) * | 2004-05-15 | 2008-05-28 | Vertex Pharma | Treating seizures using ice inhibitors |
EP2295054A1 (en) * | 2004-05-27 | 2011-03-16 | Vertex Pharmaceuticals Incorporated | Ice inhibitors for the treatment of autoinflammatory diseases |
WO2011094426A1 (en) * | 2010-01-29 | 2011-08-04 | The United State Of America, As Represented By The Secretary, Department Of Health & Human Services | Caspase inhibitors |
US9956260B1 (en) | 2011-07-22 | 2018-05-01 | The J. David Gladstone Institutes | Treatment of HIV-1 infection and AIDS |
EP3444011A1 (en) | 2014-05-12 | 2019-02-20 | Conatus Pharmaceuticals, Inc. | Treatment of the complications of chronic liver disease with emricasan |
WO2017079566A1 (en) | 2015-11-05 | 2017-05-11 | Conatus Pharmaceuticals, Inc. | Caspase inhibitors for use in the treatment of liver cancer |
WO2017117478A1 (en) | 2015-12-31 | 2017-07-06 | Conatus Pharmaceuticals Inc. | Methods of using caspase inhibitors in treatment of liver disease |
CN105853408B (en) * | 2016-04-15 | 2018-12-04 | 浙江大学 | Benzoyl amine derivative is preparing the application in Caspase-1 inhibitor |
RU2019113150A (en) | 2016-10-05 | 2020-11-06 | Новартис Аг | A COMBINATION OF COMPOSITIONS CONTAINING FXR AGONISTS FOR THE TREATMENT OR PREVENTION OF FIBROZING, CIRRHOTIC DISEASE OR DISORDER |
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US6204261B1 (en) * | 1995-12-20 | 2001-03-20 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β Converting enzyme inhibitors |
US5716929A (en) * | 1994-06-17 | 1998-02-10 | Vertex Pharmaceuticals, Inc. | Inhibitors of interleukin-1β converting enzyme |
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US7053056B2 (en) | 1998-07-02 | 2006-05-30 | Idun Pharmaceuticals, Inc. | C-terminal modified oxamyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases |
EP1179345B1 (en) | 1999-01-29 | 2009-04-08 | Senju Pharmaceutical Co., Ltd. | Inhibitors against increase in ocular tension caused by irradiation with lasers, containing 1,4-dihydropyridine derivatives |
ES2347133T3 (en) | 2000-04-24 | 2010-10-26 | Vertex Pharmaceuticals Incorporated | PROCEDURE AND INTERMEDIATES TO PREPARE SUBSTITUTED ASPARTIC ACID ACETALS. |
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EP1485107A1 (en) | 2002-02-11 | 2004-12-15 | Vertex Pharmaceuticals Incorporated | Phospholipids as caspase inhibitor prodrugs |
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-
2005
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- 2005-02-28 CA CA2557645A patent/CA2557645C/en not_active Expired - Fee Related
- 2005-02-28 WO PCT/US2005/006540 patent/WO2005085236A2/en active Application Filing
- 2005-02-28 KR KR1020067019903A patent/KR20060129069A/en not_active Application Discontinuation
- 2005-02-28 NZ NZ549665A patent/NZ549665A/en not_active IP Right Cessation
- 2005-02-28 CN CN2010106215884A patent/CN102161656B/en not_active Expired - Fee Related
- 2005-02-28 US US11/069,895 patent/US7652153B2/en not_active Expired - Fee Related
- 2005-02-28 AR ARP050100737A patent/AR047981A1/en unknown
- 2005-02-28 JP JP2007500824A patent/JP2007525503A/en active Pending
- 2005-02-28 EP EP05724143A patent/EP1718639A2/en not_active Withdrawn
- 2005-02-28 AU AU2005219861A patent/AU2005219861B2/en not_active Ceased
- 2005-03-01 TW TW101100244A patent/TW201217332A/en unknown
- 2005-03-01 TW TW094106099A patent/TWI362381B/en not_active IP Right Cessation
-
2006
- 2006-08-27 IL IL177709A patent/IL177709A0/en not_active IP Right Cessation
- 2006-09-12 ZA ZA2006/07634A patent/ZA200607634B/en unknown
- 2006-09-26 NO NO20064344A patent/NO20064344L/en unknown
- 2006-09-26 NO NO20064351A patent/NO20064351L/en not_active Application Discontinuation
-
2007
- 2007-07-03 HK HK07107033.7A patent/HK1099757A1/en not_active IP Right Cessation
-
2009
- 2009-12-03 US US12/630,350 patent/US20100105914A1/en not_active Abandoned
-
2011
- 2011-04-21 JP JP2011095553A patent/JP2011144203A/en not_active Withdrawn
- 2011-12-29 HK HK11114041.7A patent/HK1159614A1/en not_active IP Right Cessation
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2014
- 2014-05-09 JP JP2014097786A patent/JP2014140385A/en active Pending
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